Project description:CHAF1B is the p60 subunit of the chromatin assembly factor (CAF1) complex, which is responsible for assembly of H3.1/H4 heterodimers at the replication fork during S phase. Here we report that CHAF1B is required for normal hematopoiesis while its overexpression promotes leukemia. CHAF1B has a pro-leukemia effect by binding chromatin at discrete sites and interfering with occupancy of transcription factors that promote myeloid differentiation, such as CEBPA. Reducing Chaf1b activity by either heterozygous deletion or overexpression of a CAF1 dominant negative allele was sufficient to suppress leukemogenesis in vivo without impairing normal hematopoiesis.

2018-11-12 | GSE120063 | GEO

Musashi 2 regulates normal hematopoiesis and accelerates leukemogenesis

Project description:This SuperSeries is composed of the following subset Series: GSE16432: MSI2 regulates hematopoiesis and accelerates leukemogenesis GSE22773: Musashi 2 regulates normal hematopoiesis and accelerates leukemogenesis (LK and MS12-inducible) GSE22774: Musashi 2 regulates normal hematopoiesis and accelerates leukemogenesis (LSK and LK) GSE22775: Musashi 2 regulates normal hematopoiesis and accelerates leukemogenesis (Leukemia cell lines) Refer to individual Series

2010-07-21 | E-GEOD-22778 | biostudies-arrayexpress

New functional signatures for understanding melanoma biology from tumor cell lineage-specific analysis

Project description:New functional signatures for understanding melanoma biology from tumor cell lineage-specific analysis

| PRJNA280579 | ENA

A CHAF1B-dependent molecular switch in hematopoiesis and leukemia pathogenesis

Project description:A CHAF1B-dependent molecular switch in hematopoiesis and leukemia pathogenesis

| PRJNA491485 | ENA

Sustained fetal hematopoiesis causes juvenile death from leukemia: evidence from a dual-age-specific mouse model

Project description:It is not clear whether disrupted age-specific hematopoiesis contributes to the complex manifestations in leukemia patients who carry identical mutations, particularly in pediatric and adult patients with similar clinical characteristics. By studying a dual-age-specific mouse model, we demonstrate: 1) loss of Pten during the fetal-to-adult hematopoiesis switch (HSC switch) causes sustained fetal hematopoiesis, resulting in death in juvenile leukemia; 2) myeloid-biased hematopoiesis in juvenile mice is associated with the sustained fetal properties of hematopoietic stem cells (HSCs); 3) the age specificity of juvenile myelomonocytic leukemia (JMML) depends on the dosage of Pten and Nf1; 4) single-allelic Pten deletion during the HSC switch causes constitutive activation of mitogen-activated protein kinase (MAPK) in juvenile mice with Nf1 loss of heterozygosity (LOH); and 5) Nf1 LOH causes monocytosis in juvenile mice with Pten haploinsufficiency but does not cause lethality until adulthood. Our data suggest that one copy of Pten is sufficient to maintain an intact negative feedback loop of the Akt pathway and HSC function in reconstitution, despite MAPK being constitutively activated in juvenile mice with Pten+/DNf1LOH. However, two copies of Pten are required to maintain the integrity of the MAPK pathway in juvenile mice with Nf1 haploinsufficiency. Our data indicate that previous investigations of Pten function in wild type mice may not reflect the impact of Pten loss in mice with Nf1 mutations or other genetic defects. We provide a proof-of-concept that disassociated age-specific hematopoiesis contributes to leukemogenesis and pediatric demise.

2020-06-25 | GSE137152 | GEO

NF1 inactivation in adult acute myelogenous leukemia

Project description:Purpose: This study was conducted to identify novel genes with importance to the biology of adult acute myelogenous leukemia (AML). Conclusions: NF1 null states are present in 7/95=7% of adult AML and delineate a disease subset that could be preferentially targeted by Ras or mTOR-directed therapeutics.

2010-12-02 | GSE21107 | GEO

LEDGF/p75 is Dispensable for Hematopoiesis but Essential for MLL-rearranged Leukemogenesis

Project description:Mixed-lineage leukemia (MLL) represents a genetically distinct and aggressive subset of human acute leukemia carrying chromosomal translocations of the MLL gene. These translocations result in oncogenic fusions that mediate aberrant recruitment of transcription machinery to MLL target genes. The N-terminus of MLL and MLL-fusions form a complex with Lens Epithelium-Derived Growth Factor (LEDGF/p75; encoded by the Psip1 gene) and MENIN. This complex contributes to the association of MLL and MLL-fusion multiprotein complexes with chromatin. Several studies have shown that both MENIN and LEDGF/p75 are required for efficient MLL fusion-mediated transformation and for the expression of downstream MLL-regulated genes like HOXA9 and MEIS1. In light of the development of a therapeutic strategy targeting this complex, understanding the function of LEDGF/p75 in normal hematopoiesis is crucial. We generated a conditional Psip1 knockout mouse model in the hematopoietic compartment and examined the effects of LEDGF/p75 depletion in postnatal hematopoiesis and the initiation of MLL leukemogenesis. Psip1 knockout mice were viable but showed several defects in hematopoiesis, reduced colony-forming activity in vitro, decreased expression of Hox genes in hematopoietic stem cells and decreased MLL occupancy at MLL target genes. Finally, in vitro and in vivo experiments showed that LEDGF/p75 is dispensable for steady state hematopoiesis but essential for the initiation of MLL-mediated leukemia. These data corroborate the MLL-LEDGF/p75 interaction as novel target for the treatment of MLL-rearranged leukemia.

2017-09-30 | GSE104138 | GEO

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